Many neuropsychiatric disorders exhibit marked sex differences in prevalence and age of onset. Males are more likely to have disorders that arise in early childhood, including autism, schizophrenia, and learning disabilities. Females more often have disorders that arise during puberty, including anxiety and depression. This epidemiology suggests that there are sex-based neurobiological differences, which are likely to arise during development, that either directly promote specific neuropsychiatric disorders or increase the susceptibility to environmental factors that lead to such disorders. At present, no sex-based differences have been described that can fully explain the sexual dimorphism of neuropsychiatric disorders. In this proposal, we describe a sex difference in the pattern of microglial colonization of the developing rodent brain in which males have more microglia early in development, while females have more at the onset of puberty. Moreover, we demonstrate that this pattern in males is associated with both an increased inflammatory response in specific brain regions and an increased susceptibility to behavioral deficits related to the same brain regions. The pattern of sex-based anatomic and functional differences we see in our model is striking in its similarity to the sexual dimorphism of neuropsychiatric disorders in humans. To our knowledge, this is the first description of a sex-based difference in brain development that would account for the observed epidemiology of human neuropsychiatric disease. Our findings suggest a model in which sex differences in the microglial colonization of specific brain regions important for emotion and cognition at distinct windows of neural development lead to increased inflammatory responses to exogenous stimuli, which in turn cause changes in synapse remodeling in these brain regions and, ultimately, to long-term neuropsychiatric dysfunction. In this proposal, we will test key aspects of this model by determining the contribution of infection-induced microglial activation to synapse remodeling and the development of behavioral abnormalities. The results of these studies have the potential to significantly advance our understanding of human neuropsychiatric disorders. The confirmation of our model would open new opportunities for the prevention, diagnosis, and treatment of widespread and debilitating mental health disorders.

Public Health Relevance

No sex-based neurobiological differences have been described that can explain the sexual dimorphism of the development of neuropsychiatric disorders. In this proposal, we describe a sex difference in the pattern of microglial colonization of the developing rodent brain that is striking in its similarity to the sexual dimorphism of neuropsychiatric disorders in humans, and predicts the occurrence of cognitive and social dysfunction as a result of early-life infection, later in life. In this proposal, we will determinethe contribution of infection-induced microglial activation to key aspects of neural development, and to the risk of development of cognitive and/or affective dysfunction. The results of these studies have the potential to significantly advance our understanding of human neuropsychiatric disorders in males and females.